Adoptively-transferred ex vivo expanded γδ-T cells mediate in vivo antitumor activity in preclinical mouse models of breast cancer

摘要

In contrast to antigen-specific αβ-T cells (adaptive immune system), γδ-T cells can recognize and lyse malignantly transformed cells almost immediately upon encounter in a manner that does not require the recognition of tumor-specific antigens (innate immune system). Given the well-documented capacity of γδ-T cells to innately kill a variety of malignant cells, efforts are now actively underway to exploit the antitumor properties of γδ-T cells for clinical purposes. Here, we present for the first time preclinical in vivo mouse models of γδ-T cell-based immunotherapy directed against breast cancer. These studies were explicitly designed to approximate clinical situations in which adoptively-transferred γδ-T cells would be employed therapeutically against breast cancer. Using radioisotope-labeled γδ-T cells, we first show that adoptively-transferred γδ-T cells localize to breast tumors in a mouse model (4T1 mammary adenocarcinoma) of human breast cancer. Moreover, by using an antibody directed against the γδ-T cell receptor (TCR) we determined that localization of adoptively-transferred γδ-T cells to tumor is a TCR-dependant process. Additionally, biodistribution studies revealed that adoptively-transferred γδ-T cells traffic differently in tumor-bearing mice compared to healthy with fewer γδ-T cells localizing into the spleens of tumor-bearing mice. Finally, in both syngeneic (4T1) and xenogeneic (2Lmp) models of breast cancer, we demonstrate that adoptively-transferred γδ-T cells are both effective against breast cancer and are otherwise well-tolerated by treated animals. These findings provide a strong preclinical rationale for using ex vivo expanded adoptively-transferred γδ-T cells as a form of cell-based immunotherapy for the treatment of breast cancer. Additionally, these studies establish that clinically-applicable methods for radiolabeling γδ-T cells allows for the tracking of adoptively-transferred γδ-T cells in tumor-bearing hosts.